This invention relates to methods for the treatment of pain and, in particular, to the alleviation of chronic pain and its varieties, e.g., neuropathic pain, and acute persistent pain that is related to inflammation of injured body tissues.
Chronic pain is persistent pain which has long outlasted the onset of any known or suspected physical cause. It can occur after a known injury or disease or it can occur without any known physical cause whatsoever. Moreover, it can be accompanied by known tissue pathology, such as chronic inflammation that occurs in some types of arthritis, or it can occur long after the healing of the injured tissue which is suspected or known to be the cause of chronic pain. Chronic pain is a very general concept and there are several varieties of chronic pain related to the musculoskeletal system, visceral organs, skin, and nervous system.
Neuropathic pain can occur as a form of chronic pain and can also occur under acute conditions such as those following surgery or accidental trauma. Neuropathic pain call be defined as pain that results from an abnormal functioning of the peripheral and/or central nervous system. A critical component of this abnormal functioning is an exaggerated response of pain-related nerve cells either in the peripheral or in the central nervous system. This exaggerated responsiveness is manifested behaviorally as increased sensitivity to pain, i.e., as hyperalgesia or allodynia, both of which can occur in chronic neuropathic and acute inflammatory pains. An example is the pain from causalgia wherein even a light touch to the skin is felt as an excruciating burning pain (allodynia) or a normally mild pain is experienced as an excruciating one (hyperalgesia).
Neuropathic pain is thought to be a consequence of damage to peripheral nerves or to regions of the central nervous system. However, abnormal functioning of pain-related regions of the nervous system call also occur with chronic inflammatory conditions such as certain types of arthritis and metabolic disorders such as diabetes as well as with acute inflammatory conditions. Thus, many types of chronic pains that are related to inflammation as well as acute pains that are related to inflammation can be considered to be at least partly neuropathic pains.
The long term administration of narcotic analgesics to patients suffering from various types of chronic pain, e.g., causalgia, hyperesthesia, sympathetic dystrophy, phantom limb syndrome, denervation, etc., is subject to a number of serious drawbacks including the development of opiate tolerance and/or dependence, severe constipation, and so forth.
U.S. Pat. No. 4,769,372 describes a method for treating chronic pain or chronic cough in a patient while preventing or alleviating the development of constipation or other symptoms of intestinal hypomotility wherein an opioid analgesic or antitussive such as morphine, meperidine, oxycodone, hydromorphone, codeine and hydrocodone is administered to the patient together with an opioid antagonist such as naloxone, naloxone glucuronide and nalmefene glucuronide. However successful this therapeutic combination may be in inhibiting the development of constipation or other symptoms of intestinal hypomotility, it does not address the problems of tolerance and/or dependence that are associated with the long term administration of narcotic analgesics.
Other approaches to the treatment of chronic pain/neuropathic pain have included-the administration of a pharmaceutically acceptable acid addition salt or a protonated derivative of at least one microtubule inhibitor such as vinblastine, dexacetoxyvinblastine, vincristine, vindesine, leurosine and N-formyl-leurosine as disclosed in U.S. Pat. No. 4,602,909, (3S,4S)-7-hydroxy-.DELTA..sup.6 -tetrahydrocannabinol homologues and derivatives essentially free of the (3R,4R) form as disclosed in U.S. Pat. No. 4,876,276, ganglioside GM.sub.1 as disclosed in Hayes et al., Pain, 48(1992)391-396, Mao et al., Brain Res., 584(1992)18-27, 584(1992)28-35 and 588(1992)144-149 and the N-methyl-D-aspartate (NMDA) receptor antagonist, or blocker, MK801 (the compound 5-methyl-10,11-dihydro-SH-dibenzo a,d!cyclohepten-5,10-imine) and IIA966 (1-hydroxy-3-aminopyrididone-2) as disclosed in Mao et al., Brain Res., 576(1992)254-262 and Brain Res., 598 (1992) 271-278. It may be noted that MK 801 is unsuitable for use as a therapeutic due to its pronounced central nervous system neurotoxicity.
Dextrorphan, the main metabolite of the anticonvulsant dextromethorphan, and ketamine are known N-methyl-D-aspartate (NMDA) receptor antagonists but unlike MK 801, have few, if any, neurotoxic side effects. Heretofore there has been no recognition or appreciation that a nontoxic NMDA receptor antagonist would have any beneficial application to the treatment of pain or any of its varieties as well as acute pains that are likely to involve hyperalgesia/allodynia. Surprisingly, it has now been found that a non-toxic NMDA receptor antagonist such as dextrorphan exhibits significant ameliorating effects on certain types of chronic pain that result from nerve injury.